Pharmacological interactions Pharmacological with cardiacinteractions with cardiac mediated fear sensitivity mediated in binocular fear rivalry sensitivity in binocular rivalry 1,2
2,3
Cassandra D. Gould van Praag , Ryan B. Scott , Sarah N. Garfinkel
1,2
1,2
& Hugo D. Critchley
1
Poster #4324
Department of Psychiatry, Brighton and Sussex Medical School, Brighton, UK 2 Sackler Centre for Consciousness Science, University of Sussex, Brighton, UK 3 School of Psychology, University of Sussex, Brighton, UK
Introduction Introduction Cardiac signalling modulates Interoception is the sensation of the internal body and visceral organs, fear processing, with some including the heart. individuals showing inSignalling from the heart (baroreceptor activation) been proposed creasedhas fear sensitivity at systo mediate the brain-body effects of physiological arousaltoon tole relative diastole [1]. perceptual, cognitive and emotional processing. Cardiac Control of Fear in
Results Fear sensitivity
the activation Brain (CCFIB) is mediated At the level of a single heartbeat, baroreceptor (cardiac 1 the integration systole) increases intensity of fearful stimuli through , and reduces memory of 2 baroreceptor at performance . Increased accuracy in heart beat detection information is 3 cortical, limbic and brainstem associated with heightened intensity of emotion , and improved levels [2]. memory systole. Figure 1.atBrain integration of cardiac signalling. Here, wecardiac-mediated investigate the perceptual effectsaltered of heart signalling, through How is fear processing following pharmaceutibinocular rivalry. Itofwas that detection of fearful faces cal manipulation thehypothesised autonomic and affective processing systems? would be improved when binocular presentation was locked to systole This research has relevance to mechanisms underlying pain control, hyrelative to diastole, reflecting the increased emotional intensity of th pertension and anxiety.
Methods Behavioural task Participants (n = 24) were presented with rivalrous fearful and neu-
tral faces fMRI data were acquired. Fear sensitivity was determined using staircase modulation of the fearful face contrast. Two interleaved staircases were run, with stimulus presentation locked separately to systole and diastole (Figure 2).
Figure 3: Fear sensitivity under 3 drug conditions. Error bars = ± 1 SEM.
A median split by CCFIB suggests that individuals with ‘typical’ priming of fear at systole (CCFIB+) show a reduction in fear sensitivity with pregabalin, as expected for the drug. Individuals with ‘atypical’ fear priming (increased sensitivity at diastole) however, show an increase in overall fear sensitivity with pregabalin (Figure 3).
Imaging There was a significant main effect of drug in the pons and right anterior insula (Figure 4A), and significant drug*CCFIB interactions in the pons, amygdala, right anterior insula and anterior cingulate cortex (Figure 4B). A
B
Figure 2: Mean detection threshold of fear faces at systole and diastole, with participants median split into high and low interoceptive awareness. Error bars = ± 1 SEM.
Figure 4: BOLD drug effects in predefined regions of interest. (A) A main effect of drug was observed in the pons and insula, with decreased activation in pregabalin compared to placebo or losartan. (B) Drug*CCFIB interactions were observed in all hypothesised regions. Error bars = ± 1 SEM. *p < .05; ** p < .01; *** p < .001.
Figure 2: Binocular rivalry staircasing procedure. Fear contrast started at 10%, then modulated (2-down/1-up; ratio 0.5488). Over 29 minute imaging session.
Pharmaceutical manipulation Fear sensitivity was calculated for i) placebo, ii) losartan (50 mg) (treatment of hypertension) iii) pregabalin (200 mg) (treatment of anxiety). CCFIB was calculated as the difference in fear sensitivity (systole—diastole) during placebo. Imaging Scanner: 1.5T Siemens Avanto. Functional sequence: T2*-weighted EPI; TR=2210ms, TE=30ms. Resolution: 800 volumes; 36 slices; 3x3x3mm. Preprocessing: Slice time correction, re-alignment MNI, 8mm FWHM smoothing (SPM12). Random effects: i) Full factorial drug(3)*cardiac phase(2)*face detected(2); ii) Full factorial + CCFIB*drug interaction (SPM12).
References [1] Garfinkel, S. N., et al., (2014). J Neurosci, 4(19), 6573–82. [2] Gray, M. A., et al. (2009) J Neurosci, 29(6), 1817–25. [3] Béchir, M., et al. (2005). Am J Cardiol, 95(1), 129–31. [4] Baldwin, D. S., & Ajel, K. (2007). Neuropsychiatr Dis Treat, 3(2), 185–91.
Under placebo, there is a positive correlation between CCFIB and BOLD response in the amygdala. The direction of interactions are the same under losartan, however, they are reversed under pregabalin.
Conclusion Losartan and pregabalin were predicted to decrease fear sensitivity, via reduced sympathetic activation [3] and reduced excitatory neurotransmitter release [4] respectively. This trend, however, was only observed for individuals with typical cardiac priming of fear at systole (Figure 3). The relationship between CCFIB and pregabalin suggests the anxiolytic effects are mediated through the cardiac signalling pathway, notably in the brainstem and right insula (Figure 4a). The reversal of relationships between CCFIB and BOLD under pregabalin suggests cardiac priming of fear may be mediated through a balance of excitatory and inhibitory neurotransmitters (Figure 4b). The response to treatment for hypertension or anxiety may be mediated by individual differences in cardiac signalling.
Acknowledgements This work was supported by a donation from the Dr. Mortimer and Theresa Sackler Foundation to HDC and RBS, and the European Research Council to CDG, GH and SG.
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